Downregulation of TGF-β Receptor-2 Expression and Signaling through Inhibition of Na/K-ATPase

La, Jennifer; Reed, Eleanor; Chan, Lan; Smolyaninova, Larisa V.; Akomova, Olga A.; Mutlu, Gökhan M.; Orlov, Sergei N.; Dulin, Nickolai O.

doi:10.1371/journal.pone.0168363

Cited by 22 publications

(14 citation statements)

References 66 publications

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“…A number of important studies have shown the role of NKA inhibition and elevation of the [Na + ]i/[K + ]i ratio in the activation of Src-EGFR-MAPK- and Akt-mediated signaling pathways triggered by CTS, and readers are referred to a recent review which more thoroughly addresses this topic [ 83 ]. The importance of this concept is highlighted by recent data showing that NKA inhibition by CTS triggers TGFβ-induced fibrosis in cultured human lung fibroblasts via [Na + ]i/[K + ]i-mediated signaling which results in augmented expression of COX-2 [ 84 ] and downregulation of TGFβ2R [ 85 ]. Cumulatively, these studies have broadened the understanding of the role of CTS signaling through the NKA in human disease.…”

Section: Cts (Cardiotonic Steroids) Nka and Fibrosismentioning

confidence: 99%

Cardiotonic Steroids and the Sodium Trade Balance: New Insights into Trade-Off Mechanisms Mediated by the Na+/K+-ATPase

Khalaf

Dube

Mohamed

et al. 2018

IJMS

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In 1972 Neal Bricker presented the “trade-off” hypothesis in which he detailed the role of physiological adaptation processes in mediating some of the pathophysiology associated with declines in renal function. In the late 1990’s Xie and Askari published seminal studies indicating that the Na+/K+-ATPase (NKA) was not only an ion pump, but also a signal transducer that interacts with several signaling partners. Since this discovery, numerous studies from multiple laboratories have shown that the NKA is a central player in mediating some of these long-term “trade-offs” of the physiological adaptation processes which Bricker originally proposed in the 1970’s. In fact, NKA ligands such as cardiotonic steroids (CTS), have been shown to signal through NKA, and consequently been implicated in mediating both adaptive and maladaptive responses to volume overload such as fibrosis and oxidative stress. In this review we will emphasize the role the NKA plays in this “trade-off” with respect to CTS signaling and its implication in inflammation and fibrosis in target organs including the heart, kidney, and vasculature. As inflammation and fibrosis exhibit key roles in the pathogenesis of a number of clinical disorders such as chronic kidney disease, heart failure, atherosclerosis, obesity, preeclampsia, and aging, this review will also highlight the role of newly discovered NKA signaling partners in mediating some of these conditions.

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Section: Cts (Cardiotonic Steroids) Nka and Fibrosismentioning

confidence: 99%

Cardiotonic Steroids and the Sodium Trade Balance: New Insights into Trade-Off Mechanisms Mediated by the Na+/K+-ATPase

Khalaf

Dube

Mohamed

et al. 2018

IJMS

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“…increasing collagen production. Collagen protein deposition increases the extracellular matrix network [1][2][3]. The highly conserved ATP-dependent chaperone heat shock protein 90 (Hsp90) has been described as a component of the TGFβ signaling cascade [4][5][6][7].…”

Section: Accepted Manuscriptmentioning

confidence: 99%

Reduction of cardiac TGFβ-mediated profibrotic events by inhibition of Hsp90 with engineered protein

Cáceres

Chavez

Maestro

et al. 2018

Journal of Molecular and Cellular Cardiology

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Myocardial fibroblast activation coupled with extracellular matrix production is a pathological signature of myocardial fibrosis and is governed mainly by transforming growth factor TGFβ-Smad2/3 signaling. Targeting the ubiquitous TGFβ leads to cellular homeostasis deregulation with adverse consequences. We previously showed the anti-fibrotic effects upon downregulation of 90-kDa heat shock protein (Hsp90), a chaperone that associates to the TGFβ signaling cascade. In the present study, we use a fluorescent-labeled Hsp90 protein inhibitor (CTPR390-488) with specific Hsp90 binding properties to reduce myocardial pro-fibrotic events in vitro and in vivo. The mechanism of action involves the disruption of TGFβRI-Hsp90 complex, resulting in a decrease in TGFβ signaling and reduction in extracellular matrix collagen. In vivo, decreased myocardial collagen deposition was observed upon CTPR390-488 treatment in a pro-fibrotic mouse model. This is the first study demonstrating the ability of an engineered Hsp90 protein inhibitor to block collagen expression, reduce the motility of myocardial TGFβ-activated fibroblasts and ameliorate angiotensin-II induced cardiac myocardial fibrosis in vivo.

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“…Importantly, the action of ouabain was absent in p85-KO mice, thus suggesting that side-by-side with the positive inotropic effect, the treatment with Digitalis prevents pathological cardiac hypertrophy and heart failure through activation of PI3KIA [ 167 ]. Our recent study demonstrated that anti-fibrotic action of cardiac glycosides documented by the suppression of myofibroblast differentiation in TGF-β-treated human lung fibroblasts is mediated by dissipation of transmembrane gradients of monovalent cations [ 138 , 168 ]. To the best of our knowledge, the role of Na + ,K + -ATPase inhibition and the elevated [Na + ] i /K + ] i ratio in PI3K/Akt-mediated signaling triggered by CTS has not been explored yet.…”

Section: Search For Na + I K mentioning

confidence: 99%

Na+i,K+i-Dependent and -Independent Signaling Triggered by Cardiotonic Steroids: Facts and Artifacts

et al. 2017

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Na+,K+-ATPase is the only known receptor of cardiotonic steroids (CTS) whose interaction with catalytic α-subunits leads to inhibition of this enzyme. As predicted, CTS affect numerous cellular functions related to the maintenance of the transmembrane gradient of monovalent cations, such as electrical membrane potential, cell volume, transepithelial movement of salt and osmotically-obliged water, symport of Na+ with inorganic phosphate, glucose, amino acids, nucleotides, etc. During the last two decades, it was shown that side-by-side with these canonical Na+i/K+i-dependent cellular responses, long-term exposure to CTS affects transcription, translation, tight junction, cell adhesion and exhibits tissue-specific impact on cell survival and death. It was also shown that CTS trigger diverse signaling cascades via conformational transitions of the Na+,K+-ATPase α-subunit that, in turn, results in the activation of membrane-associated non-receptor tyrosine kinase Src, phosphatidylinositol 3-kinase and the inositol 1,4,5-triphosphate receptor. These findings allowed researchers to propose that endogenous CTS might be considered as a novel class of steroid hormones. We focus our review on the analysis of the relative impact Na+i,K+i-mediated and -independent pathways in cellular responses evoked by CTS.

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Downregulation of TGF-β Receptor-2 Expression and Signaling through Inhibition of Na/K-ATPase

Cited by 22 publications

References 66 publications

Cardiotonic Steroids and the Sodium Trade Balance: New Insights into Trade-Off Mechanisms Mediated by the Na+/K+-ATPase

Cardiotonic Steroids and the Sodium Trade Balance: New Insights into Trade-Off Mechanisms Mediated by the Na+/K+-ATPase

Reduction of cardiac TGFβ-mediated profibrotic events by inhibition of Hsp90 with engineered protein

Na+i,K+i-Dependent and -Independent Signaling Triggered by Cardiotonic Steroids: Facts and Artifacts

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